Hepatic fibrosis is a major phenomena of chronic alcoholic liver disease. The major objectives of this proposal is to delineate some of the fundamental mechanisms involved in this fibrotic process with special emphasis on various aspects of collagen metabolism. Viable normal and diseased human liver explants will be obtained by biopsy, or during surgery to study various aspects of collagen metabolism in tissue culture. Primary emphasis will be directed towards rate of collagen production and relative distribution of genetically distinct types of chains. Alterations in the hepatic liver collagen synthesis will be correlated with stages of alcoholic hepatitis and cirrhosis. Subsequently various agents including BUDR, collagen degradation peptides. lymphokines, and cirrhotic liver extracts will be added to culture media in an attempt to simulate the pathologic process in vivo. Cell culture of fibroblasts and injured parenchymal cells will be examined, using collagen synthesis and distribution of collagen types as the criteria. In this manner, specific cell-cell interactions as well as cell surface modifications, such as membrane phosphorylation and/or dephosphorylation and levels of cyclic AMP will be used to define alterations at the cellular level in terms of progressive liver fibrogenesis. Whenever possible, human tissue will be used although experimental rat liver cirrhosis studies with various dietary regimens including alcohol feeding will be used to supplement the above studies. Complete characterization of hepatic liver collagen must also include analysis of basement-membrane-associated collagens with special reference to alterations in the disease. The unique collagens from human liver will be examined to the extent of chain composition, molecular weight, and CNBr derived peptides from individual basement membrane collagen chains.